The compound of the invention has activity in biological systems and more particularly has activity as an antagonist to neurokinin 1 receptors.
The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes.
The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson""s disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases reviewed in xe2x80x9cTachykinin Receptor and Tachykinin Receptor Antagonistsxe2x80x9d, J. Auton. Pharmacol., 13, 23-93, 1993.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
In addition, in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.
Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in xe2x80x9cNeuropeptides, 32(1), 1-49, (1998)xe2x80x9d and xe2x80x9cEur. J. Pharmacol., 383(3), 297-303, (1999)xe2x80x9d.
Life Sci., (2000), 67(9), 985-1001 describes, that astrocytes express functional receptors to numerous neurotransmitters including substance P, which is an important stimulus for reactive astrocytes in CNS development, infection and injury. In brain tumors malignant glial cells originating from astrocytes are triggered by tachykinins via NK-1 receptors to release soluble mediators and to increase their proliferative rate. Therefore, selective NK-1 receptor antagonists may be useful as a therapeutic approach to treat malignant gliomas in the treatment of cancer.
A paper in Nature (London) (2000), 405(6783), 180-183 describes that mice with a genetic disruption of NK-1 receptor show a loss of the rewarding properties of morphine. Consequently NK-1 receptor antagonists may be useful in the treatment of withdrawal symptoms of addictive drugs such as opiates and nicotine and reduction of their abuse/craving.
NK1 receptor antagonists have been reported to have also a beneficial effect in the therapy of traumatic brain injury (Paper presented by Prof. Nimmo at the International Tachykinin Conference 2000 in La Grande Motte, France, Oct. 17-20, 2000 with the title xe2x80x9cNeurokinin 1 (NK-1) Receptor Antagonists Improve the Neurological Outcome Following Traumatic Brain Injuryxe2x80x9d (Authors: A. J. Nimnmo, C. J. Bennett, X. Hu, I. Cernak, R. Vink).
The compounds of the present invention are further useful for the treatment of benign prostatic hyperplasia (BPH), which is common in older men. BPH can be progressive and lead to urinary retention, infections, bladder calculi and renal failure. This indication has been reported in EP 01109853.0.
The present invention is a compound of the formula 
wherein
R1 is lower alkyl, lower alkoxy, pyridinyl, pyrimidinyl, phenyl, xe2x80x94S-lower alkyl, xe2x80x94S(O)2-lower alkyl, xe2x80x94N(Ra)xe2x80x94(CH2)nxe2x80x94N(Rb)2, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94N(Rc)2, xe2x80x94N(Rd)2, or a cyclic tertiary amine of the group 
or a cyclic tertiary amine of the group 
that contains one additional heteroatom, selected from N, O or S, said cyclic tertiary amine being connected to a pyrimidine ring of formula 1 or connected to said pyrimidine ring via the linker xe2x80x94O(CH2)nxe2x80x94;
R2 is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;
R3/R3xe2x80x2 are, independently from each other, hydrogen or lower alkyl;
(R4)m are, independently from each other in the case where m is not 0 or 1, halogen, trifluoromethyl or lower alkoxy;
R5 is hydrogen or lower alkyl;
R, Ra, Rb, Rc, Rd, Re, Rf are, independently from each other, hydrogen or lower alkyl;
X is xe2x80x94C(O)N(Re)xe2x80x94 or xe2x80x94N(Rf)C(O)xe2x80x94;
Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94, or xe2x80x94N(R)xe2x80x94;
n is 1,2,3 or 4; and
m is 0, 1 or 2;
and a pharmaceutically acceptable acid addition salt thereof.
The compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
The compounds of the present invention are further useful for the treatment of benign prostatic hyperplasia (BPH), which is common in older men. BPH can be progressive and lead to urinary retention, infections, bladder calculi and renal failure. This indication has been reported in EP 01109853.0.
The compounds of formula I can also be used in the form of their prodrugs, for example in form of their N-oxides. The prodrugs may add to the value of the present compounds advantages in adsorption, pharmacokinetics in distribution and transport to the brain.
Objects of the present invention are the compounds of formula I and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.